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• Genome-wide DNA-methylation assessment by MethylCap-seq and Infinium HumanMethylation450 BeadChips: an independent large-scale comparison

  DNA-methylation is an important epigenetic feature in health and disease. Two cost-efficient genome-scale methodologies to assess DNA-methylation are MethylCap-seq and Illumina's Infinium HumanMethylation450 BeadChips (HM450). However, objective information regarding the best-suited methodology for a specific research question is scant. Therefore, we performed a large-scale evaluation on a set of 70 brain tissue samples obtained from 65 glioblastoma and 5 non-tumoral brain tissues, using a gold standard free Bayesian modeling procedure. While conditional specificity was adequate for both approaches, conditional sensitivity was systematically higher for HM450. Also the genome-wide characteristics were compared, revealing that the HM450 probes assess less than 10% of the regions identified as methylated by MethylCap-seq. Hence the latter method may detect more potentially relevant DNA-methylation, defined by either functional location or previously reported differentially methylated candidate regions. Our results therefore indicate that – at least for the tissue under study - both methodologies are complementary, with a higher sensitivity for HM450, but a far larger genome-wide coverage for MethylCap-seq. Note that here only the relevant MethylCap-seq data is deposited, for the HM450 data we refer to GEO (GSE60274).

  Study EGAS00001001191

• Single_cell_measurements_to_characterise_B_cell_repopulation_in_SLE_after_rituximab_therapy__a_pilot_study

  Systemic lupus erythematosus (SLE) is a systemic autoimmune disease characterised by autoantibodies against DNA and nuclear proteins. Kidney involvement (lupus nephritis) is one of the most serious manifestations and is the leading determinant of long-term prognosis. Therapies targeting B cells (e.g. rituximab) are used in the treatment of severe lupus, including lupus nephritis. Rituximab is a monoclonal antibody that targets the CD20 surface protein on the surface of B cells. Following rituximab treatment, there is near complete depletion of B cells in peripheral blood. Peripheral blood B cells slowly return over a period of months. The speed of repopulation varies but typically B cells have returned to baseline levels between 9 and 12 months post rituximab therapy. Return of B cells may be associated with increased disease activity, but this is not always the case. For example, some patients remain in clinical remission for several years following one cycle of rituximab, despite B cell repopulation, whilst others relapse as soon as the B cell number reaches the normal range. The reasons for the different response remain unclear. The B cell subpopulations that return following B cell depleting therapy have been previously studied using flow cytometry but have never been characterised using single cell -omic technologies and thus no data on their molecular signatures are available. Previous studies have shown that naïve B cells were the predominant repopulating B-cells, indicating de novo production of B cells. Obtaining an integrated understanding of the molecular programs of these cells at the single cell level will enhance our ability to predict disease outcome, to identify patients with poorer B-cell drug responses, understand disease heterogeneity and design more effective B-cell targeted therapies approach.

  Study EGAS00001006798

• Identification of intronic sequences promoting natural skipping of ABCA4 exon 15 using long-read transcriptomics and midigene assays

  Stargardt disease is an inherited retinal disease that leads to progressive loss of vision, and is caused by biallelic variants in the ABCA4 gene. A significant proportion of ABCA4 variants of variable penetrance affect pre-mRNA splicing. Previously, we observed the exclusion of certain ABCA4 exons into the final transcript in the absence of any disease-causing variants. In this study, we explored this phenomenon that we coined natural exon skipping (NES) for the entire ABCA4 transcript, using targeted RT-PCR analysis as well as long-read transcriptome sequencing of control retina samples. For the most abundant NES event, which is skipping of ABCA4 exon 15, overlapping ABCA4 deletion constructs were employed to identify responsible cis-regulatory sequence motifs. Subsequently, antisense oligonucleotides (AONs) were designed and tested to reverse NES and restore fully-spliced ABCA4 mRNA. We identified intronic regions on each side of exon 15 that, when deleted, increased the inclusion of exon 15 in the final transcripts. Interestingly, these motifs appear to work in a synergistic manner. Further fine-mapping of these regions revealed several cis-regulatory motifs that may be responsible for inducing NES, on each side of the exon. AONs targeting these motifs unfortunately did not decrease the skipping of exon 15. In conclusion, we discovered an intriguing phenomenon that, in the absence of disease-causing variants, results in the skipping of one or more exons in the ABCA4 transcript. These NES events appear to be regulated by cis-regulatory motifs within the flanking introns. This work captured the extend of NES throughout ABCA4 transcript and the role of cis-regulatory motifs in pre-mRNA splicing.. The use of AONs targeting cis-regulatory motifs is an innovative strategy for splicing modulation, suitable for complementing future variant-specific splicing modulation therapies in ABCA4 retinopathies.

  Study EGAS50000000071

• Genetic Determinants of EGFR-Driven Lung Cancer Growth and Therapeutic Response In Vivo

  Oncogenic alterations in EGFR frequently co-occur with additional genetic alterations in EGFR-driven lung adenocarcinoma (LUAD), but how specific combinations of mutations affect tumor phenotypes and responses to targeted therapy is yet unknown. We leveraged a genetically engineered mouse model of EGFR mutant/Trp53-deficient LUAD to study the consequences of inactivating 10 different tumor suppressor genes on the fitness and tyorosine kinase inhibitor (TKI) sensitivity of these tumors. We found that loss of Keap1 is associated with a reduced response to therapy. In patients, we found that mutations in the KEAP1/NFE2L2/CUL3 pathway are associated with a significantly shorter time to treatment failure for EGFR TKI therapy compared to matched patients with wild-type KEAP1/NFE2L2/CUL3 tumors. We also analyzed whole exome sequencing data from tumor specimens before TKI treatment and at the time of treatment resistance for mutations in the KEAP1 pathway and these data are being submitted here.  

  Study phs002334

• De Novo Mutation Rates at the Single-Mutation Resolution in the Human Genome

  We developed a method to measure the origination rates of target mutations of choice and applied it to the HbS and nearby mutations in the human beta-globin (HBB) gene, as well as to the equivalent mutations in the nearly identical delta-globin (HBD) gene in sperm cells from African and European donors. Specifically, after extracting DNA from the sperm of the donors, each sample is enriched for the HbS mutation and nearby mutations by the restriction enzyme Bsu36I, which cleaves the wild-type (WT) sequence CCTGAGG at positions 16–22 of HBB and the homologous positions of HBD while leaving the HbS mutant and other mutants in these positions intact. Next, unique barcodes are attached to the DNA fragments from these Bsu36I-treated samples in order to reduce error by consensus sequencing of copies originating from the same original fragment. To determine how many target WT sequences have been removed (scanned) by Bsu36I digestion and hence to be able to calculate the de novo mutation rate, we run a second reaction in parallel for each donor. This reaction involves the same steps as the former reaction except for digestion by Bsu36I (Bsu36I-untreated). Spiking into the Bsu36I-treated and untreated samples known amounts of mock HBB-like DNA molecules that are fully resistant to Bsu36I digestion allows to calculate in the sequence analysis stage the Bsu36I-enrichment score based on the change in their frequency between the two treatments, which in turn is used to calculate the number of scanned WT sequences. Our results show significant correspondence between de novo mutation rates and past observations of alleles in carriers, showing that mutation rates vary substantially in a mutation-specific manner that contributes to the site frequency spectrum. We also found that the overall point mutation rate is significantly higher in Africans than Europeans in the HBB region studied. Finally, the rate of the 20A>T mutation, called the “HbS mutation” when it appears in HBB, is significantly higher than expected from the genome-wide average for this mutation type. Nine instances were observed in the African HBB ROI, where it is of adaptive significance, representing at least three independent originations, and no instances were observed in the European HBB ROI or in the European or African HBD ROI.12 consented subjects; samples from two subjects were pooled

  Study phs002391

• Transcriptional_profiling_of_tauopathies_in_human_IPS_derived_neurons

  This project is a pilot study, in collaboration with Maria Grazia Spillantini and Mariangela Iovino (Cambridge Centre for Brain Repair), to investigate the utility of IPS-derived neurons for the study of neurodegenerative disorders. Our aim is to characterise the transcriptional consequences of tauopathies using neurons derived from differentiated IPSCs as a model system. We will use IPS cells derived from six individuals, four with known mutations in the tau protein, 2 without. RNA will be extracted at Day 0 and Day 65 of differentiation by which time the neuronal tauopathy is apparent. RNA will be extracted and the transcriptome of each line characterised using RNAseq. We will then search for genes that are differentially expressed between the transcriptomes of individuals with tau mutations versus those in controls. My lab will analyse the RNAseq data, comparing both affected and controls and both time-points, to establish candidate genes. Darren Logan’s lab, along with our collaborators, will experimentally verify and further investigate these genes in additional lines and animal models. From this analysis we will generate a list of candidate genes that are differentially expressed between cases and controls. This study will not only help us understand the molecular basis of tauopathies, but also identify gene candidates for biomarkers of neurodegenerative disease. It will serve as a proof of principle for future planned studies into generating and transcriptomically analysing an allelic series of Tau mutations in IPSCs with a controlled genetic background.This data is part of a pre-publication release. For information on the proper use of pre-publication data shared by the Wellcome Trust Sanger Institute (including details of any publication moratoria), please see http://www.sanger.ac.uk/datasharing/

  Study EGAS00001000382

• DAC Fondazione Michelangelo

  This is the DAC responsible for granting access to sequencing data generated by Fondazione Michelangelo

  Dac EGAC50000000179

• Molecular profiling of longitudinally observed small colorectal polyps: a cohort study

  Knowledge of the natural history of colorectal adenomas is limited because these lesions are removed upon detection. The few studies in which small adenomas have been left in situ for a limited period of time have shown that most lesions remain stable or even completely vanish. Lesions that have grown in size more often turn out to be advanced adenomas when resected. Specific DNA copy number changes (cancer associated events or CAEs) are associated with progression of adenomas to cancer. The aim of the study was to evaluate whether growth of small colorectal polyps left in situ is associated with specific molecular features.

  Study EGAS00001003284

• Clonal relationships of ductal carcinoma in situ and recurrent invasive breast cancers defined by genomic analysis

  Ductal Carcinoma In Situ (DCIS) is the most common form of pre-invasive breast cancer and despite treatment a small fraction (5-10%) of DCIS patients present with invasive disease many years later. A fundamental biologic question is whether the invasive disease recurring in the same breast is established by tumor cells in the initial DCIS or represents new unrelated disease. To address this question, we performed genomic analyses on the initial pure DCIS lesion and paired invasive recurrent tumors in 95 patients together with single cell DNA sequencing in a subset of cases. Our data shows that in 75% the invasive recurrence was clonally related to the initial DCIS, suggesting that the tumor cells were not eliminated during the initial treatment with surgery +/- radiotherapy. Surprisingly however, 18% were clonally unrelated to the DCIS, representing new independent lineages, and 7% of cases were ambiguous. Our findings show that although DCIS is often the precursor of invasive recurrence, a significant fraction of invasive recurrences are unrelated to the initial DCIS. This knowledge is essential for accurate risk evaluation of DCIS treatment de-escalation strategies and the identification of predictive biomarkers.

  Study EGAS00001005784

• Clonal relationships of ductal carcinoma in situ and recurrent invasive breast cancers defined by genomic analysis

  Ductal Carcinoma In Situ (DCIS) is the most common form of pre-invasive breast cancer and despite treatment a small fraction (5-10%) of DCIS patients present with invasive disease many years later. A fundamental biologic question is whether the invasive disease recurring in the same breast is established by tumor cells in the initial DCIS or represents new unrelated disease. To address this question, we performed genomic analyses on the initial pure DCIS lesion and paired invasive recurrent tumors in 95 patients together with single cell DNA sequencing in a subset of cases. Our data shows that in 75% the invasive recurrence was clonally related to the initial DCIS, suggesting that the tumor cells were not eliminated during the initial treatment with surgery +/- radiotherapy. Surprisingly however, 18% were clonally unrelated to the DCIS, representing new independent lineages, and 7% of cases were ambiguous. Our findings show that although DCIS is often the precursor of invasive recurrence, a significant fraction of invasive recurrences are unrelated to the initial DCIS. This knowledge is essential for accurate risk evaluation of DCIS treatment de-escalation strategies and the identification of predictive biomarkers.

  Study EGAS00001006306